Valued Relative and 2 Strong Loyalists Die in Damascus Attack Asef Shawkat was a brother-in-law to President Bashar al-Assad of Syria and a top enforcer in his embattled government, a loyalist so committed that he stood by the Assad family even after he was reportedly shot by the president's younger brother. With Mr. Shawkat in the command center of the government's campaign to crush the Syrian opposition was a who's who of Mr. Assad's inner circle, including his defense minister and a former defense minister. All three were killed Wednesday by the explosion of a bomb inside what should have been among the most secure rooms in Damascus. The attack dealt a grave blow to the leadership of the government's war machine and struck an even bigger psychological one to its ability to project a sense of power and cohesion. Other top officials, including the interior minister, were wounded, Syrian state news media reported. "Bashar today can no longer trust almost anyone who is close to him, and that is going to send a shiver through his inner circle and their confidence," said Joshua Landis, a Syria scholar at the University of Oklahoma. In a government that always entrusts top security posts to close relatives, the death of Mr. Shawkat was the most critical loss. He was the husband of Mr. Assad's only sister, a former spy chief and the deputy defense minister. After the deaths of two brothers, Mr. Assad has only one left - Maher al-Assad, the chief of the elite praetorian guards charged with protecting the family. His whereabouts on Wednesday were unknown. With the ranks of his male siblings depleted, Mr. Assad relies on his cousins, like the business mogul Rami Makhlouf and his brother Hafez Makhlouf, a senior intelligence official, along with Dhu al-Hemma al-Shalish, the director of presidential security. Mr. Shalish, in particular, has risen in the thinning ranks of the Assad inner circle as the key financier and organizer of the paramilitary forces known as Shabiha. Mr. Shalish and his immediate family "were looked at as lowlife no-goodniks a year ago, but today they have been catapulted into the ranks of the inner circle because they are willing to do the dirty work for the regime," Mr. Landis said. There are only so many family members. The bombing came days after high-level defections from Mr. Assad's government and open combat on the streets of the capital. "This is a real turning point," said Paul Salem, director of the Carnegie Middle East Center in Beirut, noting that the collapse of the Assad government could be weeks away instead of the many months that had been the view among analysts. It is a body blow, a failure on a massive scale. The regime is still there, but to say that it is staggering is an understatement. Mr. Shawkat, in particular, was said to have played a central role during the uprising. He was an enforcer who also served as one of the government's chief negotiators with armed opposition groups in cities like Zabadani and Homs. He began his career in the service of the Assad family as a Syrian Army volunteer, rising through the ranks. His courtship of Mr. Assad's sister, Bushra, was bitterly opposed by Mr. Assad's brother Basil, who died in a 1994 car crash. Afterward, Mr. Shawkat eloped with her. In 1999, he was reportedly shot by Maher al-Assad in a family squabble. But he nonetheless succeeded in bonding with the father of the clan, former President Hafez al-Assad, as well as his son and heir, Bashar. Their favor was considered a sign of Mr. Shawkat's clout. A 1999 State Department cable released by WikiLeaks described him as "tough, extremely intelligent, well-read, quiet and a self-starter." In 2006, United States officials concluded he was a "key architect of Syria's domination of Lebanon" and froze his assets. Mr. Shawkat kept a low public profile and mixed ruthlessness with pragmatism. He alternately held out rewards and the threat of violence as he sought to squash the uprising. Leaders in the mountain city of Zabadani said in January that after six days of intense fighting there, Mr. Shawkat had personally negotiated a short-lived truce with local council members. The identities of the others killed in the blast were a reminder of the fragile alliances with members of the Christian minority and with a Sunni Muslim majority elite that have helped the Assad family and their small Alawite Muslim sect continue to dominate Syria's fractious populace. The defense minister, Gen. Dawoud A. Rajha, 65, was the most powerful Christian in the government. He was hastily named to his post last August as the government sought to fortify itself against the escalating uprising. He replaced Gen. Ali Habib Mahmoud, who was said to have disagreed with President Assad over his handling of the uprising. Mr. Rajha, chosen for his loyalty, had no such compunctions, and in March the United States imposed sanctions on him for his role in the repressions as well. Maj. Gen. Hassan Turkmani, 74, was the reported leader of the crisis cell that Mr. Assad had assembled to handle the uprising. He commanded a mechanized division in the 1973 Arab-Israeli war, later served as army chief of staff, and in 2004 served a stint as defense minister. But the major blow to the Assad government, said Peter Harling, a Syria researcher with the International Crisis Group, was not the loss of the individuals. This is a regime of networks, not institutions. They are all senior officials, but absolute power tends to be vested elsewhere," he said. What counts is this symbolism of all of this. David D. Kirkpatrick reported from New York, and Kareem Fahim from Cairo.